Comparison of the TNM9th and 8th editions for localized and locally advanced anal squamous cell carcinoma treated nonsurgically and proposal of a new stage grouping system

Abstract Objective To compare the survival discrimination of the TNM9th and 8th editions for localized and locally advanced anal squamous cell carcinoma (ASCC) treated nonsurgically and suggest a simple revised staging system with data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods Overall survival (OS) was the primary endpoint. Survival comparisons between the T and N stages and the different staging systems were performed using the Kaplan–Meier method and log‐rank test, followed by correlation analysis and variable importance analysis (VIA). Additionally, multivariate analysis was employed to identify significant predictors, which were further visualized using a nomogram. Finally, calibration curve, C‐index, and decision curve analysis (DCA) were applied to assess the performance of the different staging systems. Results A total of 5384 patients with ASCC were analyzed, revealing superior discrimination OS by the TNM9th edition compared to that by the TNM8th edition. Multivariate analysis identified the T and N stages as significant OS predictors (all p < 0.001). However, ambiguity persisted in stage III subgroups within the TNM9th edition, showing OS times of 102 months for stage IIIA disease, 88 months for stage IIIB disease, and 128 months for stage IIIC disease (all p > 0.05). Correlation analysis demonstrated an increased correlation for the T stage between the TNM8th and 9th editions (ρ value from 0.7 to 0.89), while the N stage correlation decreased (ρ value from 0.84 to 0.56). VIA and the prognostic nomogram highlighted the greater importance of the T stage over the N stage. Based on these findings, a new staging system was developed, and its clinical utility was confirmed through calibration curves, C‐index values (from 0.598 to 0.604), and DCAs. Conclusions Our new staging system exhibited slightly better prognostic value compared to the TNM9th staging systems for nonmetastatic ASCC and warrants further validation.


| INTRODUCTION
2][3] The GLOBOCAN 2020 study reported >50,000 new cases of anal carcinoma, with nearly 20,000 related deaths occurring worldwide in 2020. 4Anal squamous cell carcinoma (ASCC) is the predominant type of anal carcinoma among all histological subtypes. 5Until the research by Nigro et al., surgical resection was the historical curative treatment option. 6ince that study publication, the paradigm for treating localized and locally advanced ASCC has shifted to external beam radiation therapy (EBRT) combined with concurrent chemotherapy (CTx), 7,8 along with local excision only for a small proportion of patients with early-stage ASCC without high-risk factors. 9The long-term follow-up results of the landmark Radiation Therapy Oncology Group (RTOG) 0529 trial also confirmed the survival benefits of concurrent chemoradiotherapy (CCRT), revealing an overall survival (OS) rate of 76% and 68% at the 5-and 8-year follow-ups, respectively. 10However, the degree of positive survival outcomes for patients with localized and locally advanced ASCC treated by CCRT can vary depending on several factors, particularly the cancer stage.
The classical American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) system is a widely accepted staging system in oncology.The TNM system helps to decide between different treatment options according to the disease stage, enabling satisfactory prognostic prediction in daily clinical practice. 11,124][15] Compared with the TNM6th and 7th editions, the TNM8th and 9th editions do not have any changes in the definition of T classification, whereas major revisions are present in the N definition.In particular, the involvement of the external iliac lymph nodes (LNs) is considered a site of regional disease in the TNM8th and 9th editions, but it was classified as a site of distant metastasis in the previous editions.Furthermore, in the case of patients diagnosed using TNM8th staging, previous data from the National Cancer Database (NCDB) indicated that patients with stage IIIA anal cancer (T1-2N1M0) had a better prognosis than those diagnosed with stage IIB anal cancer (T3N0M0).This finding is a paradox to the common understanding that higher staging is associated with a worse prognosis.Thus, the TNM9th staging system introduced certain adjustments, including (1) the redefinition of stage IIB as T1-2N1M0 disease, (2) the redefinition of stage IIIA as T3N0-1 M0 disease, and (3) the elimination of stage 0 disease. 15However, this update has not yet been confirmed in other cohorts.
In this study, we first validated the clinical usefulness of the TNM9th staging system for patients with localized and locally advanced ASCC who underwent nonsurgical treatment.Further, we compared the efficacy of the TNM9th and 8th staging systems.Finally, a simple staging system was suggested for patients with localized and locally advanced ASCC based on data acquired from the Surveillance, Epidemiology, and End Results (SEER) database.

| Patient selection
This retrospective study retrieved data spanning 2004 to 2018 from the SEER 18 population-based registries 88 months for stage IIIB disease, and 128 months for stage IIIC disease (all p > 0.05).Correlation analysis demonstrated an increased correlation for the T stage between the TNM8th and 9th editions (ρ value from 0.7 to 0.89), while the N stage correlation decreased (ρ value from 0.84 to 0.56).VIA and the prognostic nomogram highlighted the greater importance of the T stage over the N stage.
Based on these findings, a new staging system was developed, and its clinical utility was confirmed through calibration curves, C-index values (from 0.598 to 0.604), and DCAs.
Conclusions: Our new staging system exhibited slightly better prognostic value compared to the TNM9th staging systems for nonmetastatic ASCC and warrants further validation.

K E Y W O R D S
anal squamous cell carcinoma, comparison, overall survival, TNM (SEER* Stat 8.3.6), which cover nearly half of the United States population, 16 using the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) site code of C21.0-9.The following inclusion criteria were used in recruiting the patients for this study: (1) a confirmed histopathological diagnosis of ASCC; (2) primary diagnosis of nonmetastatic ASCC; (3) age ≥18 years; and (4) a clear indication that the ASCC was treated nonsurgically.The major exclusion criteria were as follows: (1) more than one primary cancer indicated in the registry; (2) treatment other than EBRT ± CTx; and (3) ambiguous data about the TNM stage and survival time <1 month.The Institutional Review Board (IRB) of Zhejiang Provincial People's Hospital determined that the data in this dataset contained no personal identifiers and were publicly available after permission.Therefore, a formal IRB review was waived.

| Data processing
In the initial database, tumors were registered based on the AJCC TNM6th edition for patients with ASCC diagnosed between 2004 and 2015, the SEER combined stage for those diagnosed in 2016 and 2017, and the Derived extent of disease (EOD) 2018 T and N (2018+) for those diagnosed after 2018.The definitions for the stages diagnosed after 2016 are available at https:// seer.cancer.gov/ seers tat/ varia bles/ seer/ ajcc-stage/ .Patients were then restaged according to the stage categories of the TNM8th and 9th editions.Furthermore, in the TNM6th edition and patients diagnosed in 2016 and 2017, the involvement of the external iliac LNs was defined as distant metastasis.This aspect could not be identified and further processed from the original dataset.Sixty years was set as the cutoff point for age comparison according to the results of another SEER study. 17The diagnosis period was categorized as a ternary factor and divided into 2004-2008, 2009-2013,  and 2014-2018.SEER registry was defined as a binary factor and segregated as California and NonCalifornia. 18ther variables were processed as described in our previous studies. 19-21

| Statistical analysis
Survival data, including survival status (alive or dead) and survival time in months, were also obtained from the database.OS was determined as the duration between the day of ASCC diagnosis and the day of death due to any reason or the last follow-up day recorded in the database.Baseline characteristics of the patients were summarized using descriptive statistics and frequency tables.Survival curves were plotted using the Kaplan-Meier method and log-rank test.A higher likelihood ratio chi-square value in the Cox regression model indicated better homogeneity in the staging discrimination. 22Correlation between the T and N stages and the different tumor stages and the importance of the two variables (T and N stages within the different staging systems) were analyzed using the Spearman rank correlation coefficient (ρ) and random forest algorithm with the "corrplot" and "randomForestSRC" R packages.The Cox proportional hazard regression model was employed to evaluate the prognostic variables in multivariate analysis using the significant factors identified by univariate analysis (expressed via hazard ratio [HR] and 95% confidence interval [CI]).Furthermore, a prognostic nomogram for predicting 5-and 10-year OS was constructed based on the multivariate analysis.Lastly, the different staging systems were evaluated using Harrell's concordance index (C-index) values, calibration curves, and decision curve analyses (DCAs) as described in our previous study. 20tatistical analyses were performed via the Statistical Package for the Social Sciences software (version 25.0;IBM Corporation, Armonk, NY, USA) and R software (version 3.6.2;https:// www.r-proje ct.org, Institute for Statistics and Mathematics, Vienna, Austria).Survival curves were plotted using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA).A two-sided statistical significance level of p < 0.05 was employed.

TNM8th and 9th editions
Figure 1 illustrates the survival curves based on the different staging groups with detailed statistical results.Overall, the 5-and 10-year OS rates were 69.7% (95% CI, 0.683-0.711)and 59.7% (95% CI, 0.557-0.617),respectively, and the median OS time was not reached at the last follow-up.
Briefly, in the AJCC TNM8th edition, a paradox was observed between stage IIB and IIIA diseases (median OS: 125 months for stage IIB disease vs. not reached for stage IIIA disease), with this difference exhibiting statistical significance (p < 0.001; Figure 1A).Furthermore, no statistical difference was identified in OS between stage IIIB and IIIC diseases (median OS: 88 months for stage IIIB disease vs. 91 months for stage IIIC disease, p = 0.434).In the updated AJCC TNM9th edition (Figure 1B), improved discrimination with a significant difference was observed between stage IIB and IIIA diseases (median OS: not reached for stage IIB disease vs. 102 months for stage IIIA disease; p < 0.001).However, certain ambiguity was still demonstrated among the subgroups of stage III diseases (i.e., 102 months for stage IIIA disease vs. 88 months for stage IIIB disease vs. 128 months for stage IIIC disease), although these findings were not significant.Thus, we aimed to improve the survival discrimination further using the AJCC TNM9th edition.T A B L E 1 (Continued)

| Analysis of T and N stages
Initially, we performed a correlation analysis between the T and N stages and the TNM8th and 9th staging systems (Figure 2A).The analysis revealed an increased correlation (ρ value from 0.7 to 0.89) for the T stage in the TNM8th and 9th staging systems, respectively.In contrast, the N stage showed a decreased correlation in the TNM8th and 9th staging systems.Next, variable importance analysis (VIA) was conducted by applying a random forest algorithm to the enrolled patients (Figure 2B).Compared with the N stage, the T stage had a more prominent prognostic influence on OS (the relative importance rate [RIR] for the N stage was 5%, whereas the RIR for the T stage was 100%).A similar result was also obtained when VIA was conducted between the TNM8th and 9th staging systems (Figure 2C).Furthermore, univariate and multivariate Cox regression analyses were performed to identify predictive factors for OS (Table S1).We abandoned the different staging systems in the multivariate Cox regression model due to the multicollinearities between the T and N stages and the staging systems (Figure 2A).Ultimately, a nomogram based on the multivariate Cox regression model results was constructed and evaluated (Figure 3).The T stage was revealed as the most important prognostic parameter for OS estimation, whereas the N stage was the penultimate component in the nomogram.

| Proposal of a simple stage grouping system
Based on the above-mentioned results and the increasing number of patients with early-stage anal cancer receiving definitive treatments, the continuous prognostic importance of the T stage was emphasized.A simplified staging system, without modifications to the T and N stage definitions, was proposed as depicted in Figure 2D.In this system, patients with T1 disease were categorized as stage I (T1N0-1 M0), irrespective of regional LN status.T2 disease was classified as stage II, with patients exhibiting negative LNs classified as stage IIA (T2N0M0) and those exhibiting positive LNs as stage IIB (T2N1M0).T3-4 diseases were defined as stage III, with patients exhibiting negative LNs classified as stage IIIA (T3-4N0M0) and those exhibiting positive LNs as stage IIIB (T3-4N1M0).A tighter correlation for the T stage was observed in the proposed system compared to the TNM8th and 9th systems (Figure 2A).The proposed system also placed greater importance on OS in the random forest algorithm (Figure 2C).IIIB in the proposed staging system.A survival curve based on the proposed system is shown in Figure 2E.Except for the nonsignificant survival benefit of stage IIIA over stage IIIB patients (median OS: 102 months vs. 89 months; p = 0.200), other group comparisons showed significant differences (p < 0.05).

| Comparison and validation of the proposed staging system
The C-index values of the TNM8th and 9th staging and the proposed staging systems for predicting 5-year OS were 0.586, 0.598, and 0.604, respectively.The calibration curves indicated that the proposed staging system had the smoothest trend and the most satisfactory agreement between the prediction and actual survival in our patient population (Figure 4).The DCAs also suggested that the proposed staging system gained the most benefits for OS prediction within all threshold probabilities and provided greater positive net benefit than the "all" or "none" strategies for the enrolled patients (Figure 5).

| Subgroup analysis for ASCC patients diagnosed between 2014 and 2018
The TNM9th anal cancer staging system, based on NCDB data from 2014 to 2018, 15   curves (Figure S3).Subgroup DCAs reconfirmed the proposed system's slight net benefit over the TNM8th and TNM9th systems, consistent with the C-index outcomes (Figure S4).

| DISCUSSION
In this study, correlation analysis and VIA between the T and N stages and the two AJCC TNM staging systems demonstrated unsatisfactory survival outcomes at certain sub-stages, particularly stage III ASCC.Therefore, we investigated whether we could improve the prognostic usefulness of the widely accepted TNM system for patients with nonmetastatic ASCC.
After reviewing the updates from the TNM6th to 9th staging systems, major changes focused on regional LNs were observed.For example, the N2 and N3 categories in the older TNM6th and 7th staging systems based on the locations of positive LNs were removed, and new definitions of N1a, N1b, and N1c were provided in the later editions.4][15] Based on the two main guidelines on the delineation of treatment volumes for EBRT, 23,24 the drainage area of regional LNs, including the inguinal, mesorectal, superior rectal, internal iliac, obturator (N1a), and external iliac (N1b) LNs, were recommended for irradiation except in selected patients with early stage, node-negative ASCC.In the contemporary RTOG 0529 trial, a prescribed radiotherapy (RT) dose of 50.4-54Gy via intensity-modulated RT (IMRT) was administered in patients with positive LNs, whereas an RT dose of 42 Gy was provided to those with negative LNs.Moreover, long-term follow-up analysis demonstrated a cumulative incidence rate of 16% for local-regional failure (LRF) at the 5-and 8-year follow-ups.Additionally, distant metastasis rates of 16% and 22% were reported at the 5-and 8-year follow-ups, respectively, indicating appropriate RT dosing in regional LNs. 10 Furthermore, advanced EBRT technologies, such as volumetric arc therapy (VMAT), helical tomotherapy (HT), and proton therapy, have facilitated satisfactory coverage of the RT doses not only to primary tumors but also to regional LNs. 25,26 retrospective study by Gleeson et al. compared the dosimetric distributions of VMAT and HT for the definitive treatment of localized and locally advanced ASCC.The study results showed that the two treatment modalities achieved high-quality RT plans, with HT exhibiting advantages in the dose distribution to the small bowel and bladder.However, the VMAT modality was associated with a significantly shorter delivery time than HT.27 The emphasis on the prognostic effect of regional LN (N stage) and not the original tumor size (T stage) might be attributed to the findings of a series of post hoc analyses of prior prospective trials.For example, data from the RTOG 9811 trial demonstrated that positive LNs were an independent prognostic factor for decreased OS and disease-free survival (DFS), while tumor diameter only showed a significant effect on DFS.28 Similarly, in the ACT-I trial conducted in the UK, positive LNs were indicated as a prognostic indicator for significantly higher LRF, tumor-specific death, and lower OS.29 In the European Organization for Research and Treatment of Cancer 22,861 trial, clinically positive LNs not only significantly predicted poor OS but also forecasted decreased loco-regional control.30 In our study, the multivariate Cox regression analysis supported the prognostic value of regional LNs in the enrolled patients, consistent with the previous results.However, the T stage was revealed as the most prognostic factor for OS in our study.A similar finding supporting the prognostic effectiveness of the T stage was reported from the NCDB data analysis mentioned earlier, which included 12,968 cases of anal cancer.15 Correspondingly, another retrospective cohort study from France involving 82 patients with ASCC who underwent EBRT ± CTx indicated that the T stage was an independent prognostic variable for progression-free survival (p = 0.04).31 A 2021 SEER database study reported that tumor size had a significant prognostic value for OS in 2458 patients with stage I-IV anal cancer.However, the cutoff value of the tumor size was not as per the T stage definition in the TNM staging manual.17 Considering that most patients with localized and locally advanced ASCC would be recommended EBRT ± CTx, the clinical stage (and not the pathological stage) is the primary factor in clinical decision-making.Thus, accurate T staging based on the longest tumor diameter obtained on radiological imaging is crucial.32 Furthermore, compared with abdominal computed tomography (CT), pelvic magnetic resonance imaging (MRI) employing different scanning sequences on one of the three conventional planes is considered advantageous for clinical T categorization, 33,34 whereas the detection of metastatic regional LNs remains controversial in the current literature.As reported in previous studies, proper criteria for detecting metastatic LNs solely based on the size illustrated on a short axis might be prone to error, [34][35][36] accompanied by the potential partial visualization of the inguinal nodes and missing detection of metastatic nodes due to the improper placement of the saturation band used in abdominal MRI.32 In this field, positron emission tomography (PET/CT) has been shown to offer superior diagnostic performance for metastatic LNs compared to CT and MRI. A evious meta-analysis revealed that PET/CT resulted in a nodal staging change in 28% (95% CI, 0.18-0.38) of ASCC patients, while the TNM stage was altered in 41%.37 Additionally, PET/MRI has shown benefits for anal cancer with molecular imaging advantages and excellent soft tissue contrast resolution.38 This study has several limitations that need to be considered.Firstly, the present study was a retrospective analysis with patients enrolled over a wide time period (2004-2018), highlighting the need for further prospective validation with larger sample sizes.Moreover, the proposed staging system was specifically designed for localized and locally advanced ASCC patients who underwent nonsurgical treatment and was solely based on data from the SEER database, indicating the necessity for expanded confirmation across all histological types of anal cancer and integration with metastatic disease staging in external cohorts.Secondly, certain crucial parameters, including the human papillomavirus (HPV) infection status, metastasis to the external iliac LNs in patients registered between 2004 and 2017, initial tumor staging using advanced imaging techniques like MRI, PET/CT and PET/ MRI, performance status, tumor marker levels, nutritional status, and treatment failure pattern, were not available in the current SEER database.Lastly, advancing treatment options for ASCC patients undergoing CCRT have introduced unknown treatment-related variables, including different EBRT patterns (traditional two-dimensional RT or advanced techniques like IMRT or VMAT), concurrent CTx regimens including mitomycin C and 5-fluorouracil or capecitabine, as well as immunotherapies, potentially introducing bias in the final inferences.To date, a deescalation treatment strategy has been applied for patients having head and neck SCC with positive HPV status; thus, the application of this treatment approach for ASCC is worth future investigation.

| CONCLUSIONS
This study observed improved prognostic performance of the AJCC TNM9th edition over the 8th edition for patients with localized and locally advanced ASCC undergoing nonsurgical treatment.Detailed comparative analyses between the T and N stages and the TNM staging systems led to the proposal of a revised staging system that emphasizes the continuous prognostic value of the T stage.Subsequent subgroup analysis of patients diagnosed from 2014 to 2018, along with calibration curves, C-index values, DCAs, further confirmed the superiority of the proposed staging system over the TNM9th staging system.Given the critical importance of accurate cancer staging in oncology, large-scale validation of this new staging system for patients with ASCC is recommended in future studies.
Figure 2E demonstrates the distribution of patients enrolled based on different staging systems.The proposed system introduced a major change for 194 patients with T1N1M0 ASCC, downstaging them from stage IIB in the TNM9th system to stage I. Additionally, T4N0-1 M0 patients (stage IIIB-C in the TNM9th staging) were uniformly classified as stage F I G U R E 1 Overall survival (OS) of patients with localized and locally advanced anal squamous cell carcinoma who received nonsurgical treatment according to (A) the AJCC TNM8th and (B) TNM9th staging systems.

F I G U R E 2
(A) Correlation coefficients between the T and N stages and the three different staging systems.(B) Variable importance analysis between the T and N stages in the enrolled patients.(C) Variable importance analysis of the TNM8th and TNM9th staging and the proposed staging systems in the included patients.(D) The proposed staging system for patients with localized and locally advanced anal squamous cell carcinoma who received nonsurgical treatment.(E) The proportion of patients diagnosed using the three different staging systems.(F) OS analysis of the enrolled patients based on the proposed staging system.

F I G U R E 3 AF I G U R E 4
nomogram predicting the OS of the patients with ASCC according to the multivariate analysis.Calibration curves for predicting the 5-year OS of the patients based on the three different staging systems.(A) TNM8th staging system.(B) TNM9th staging system.(C) The proposed staging system.

F I G U R E 5
Decision curve analysis of the enrolled patients according to the three different staging systems.
Baseline clinicopathological and treatment features of patients with localized and locally advanced anal squamous cell carcinoma who underwent nonsurgical treatment.